Ras oncogenes are part of a large family of related proteins. Many of these Ras-related proteins are suspected of playing a role in tumorigenic transformation. Indeed, certain Ras-related proteins appear to serve as downstream components of Ras signaling and transformation.We have focussed on those proteins which not only share structural homology to Ras, but also undergo the same type of lipid processing as Ras, farnesylation. Drugs directed at inhibiting farnesylation (farnesyl transferase inhibitors or FTIs), which is essentail for Ras function, are currently in clinical trials at the NIH. Consequently, understanding the overall importance of other farnesylated proteins in growth and development may have considerable clinical relevance.We have found that the novel Ras-related proteins Rho6 and Rho7 are also farnesylated and appear to act as inhibitors of certain aspects of Ras transformation. Moreover, the inhibition is dependent upon Rho6/7 farnesylation. Studies are underway to determine if these proteins may play a role as tumor suppressors. If so, the long-term use of FTIs may serve to inadvertantly inactivate tumor suppresors.We are also examining a novel Ras-related protein sub-family identified by data base searching which we have designated Rig. There are three members, Rig1, Rig2, and Noey2. These proteins mediate cell death and tumor inhibition in a farnesylation-dependent manner and are frequerntly down-regulated during tumor development. We are currently attempting to define a mechanism of action as well as characterizing a further two novel Rig-related proteins. These studies have been facilitated by a successful two-hybrid screen to identify Rig-interacting proteins. We have also initiated experiments in a zebrafish backgound to determine the role of these proteins in development. It appears that Rig expression is essential for zebrafish development.